Vinylheterocycles as rho-associated coiled-coil kinase (ROCK) inhibitors
a technology of rho-associated coiled-coil kinase and vinylheterocycles, which is applied in the direction of respiratory disorders, drug compositions, organic chemistry, etc., can solve the problems of systemic inhibition of rock, significant hypotension risk, and severe adverse events
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example 1
hoxy-2-(4-(2-(pyridine-4-yl)vinyl)-[2,4′-bipyrimidin]-2′-yl)isoindoline (Ex. 1)
[0268]
Step 1: 2-(5-Methoxyisoindolin-2-yl)pyrimidine-4-carbonitrile (1-3)
[0269]To a stirred mixture of 2-chloropyrimidine (1-1, 1.5 g, 10.8 mmol) and 5-methoxyisoindoline hydrochloride (1-2, 2.0 g, 10.8 mmol) in anhydrous acetonitrile (40 mL) was dropwise added N,N-diisopropylethylamine (4.14 mL, 23.76 mmol). The reaction mixture was stirred for 3 h at 80° C. The resulting solution was concentrated under vacuum and then triturated with water, and filtered. The filter cake was thoroughly washed with water and dried under vacuum to give brownish product 1-3 (2.45 g, yield: 90%). MS (ESI+): m / z: 253.1 (M+H)+.
Step 2: Methyl 2-(5-methoxyisoindolin-2-yl)pyrimidine-4-carbimidate (1-4)
[0270]To a stirred slurry of 1-3 (1.2 g, 4.8 mmol) in anhydrous methylene chloride (25 mL) was successively added acetyl chloride (3.4 mL, 47.6 mmol) and anhydrous methanol (2.9 mL, 71.4 mmol) at 0° C. The reaction mixture was slowl...
example 2
(2-(1H-Pyrazol-3-yl)vinyl)-[2,4′-bipyrimidin]-2′-yl)-5-methoxyisoindoline (Ex. 2)
[0274]
Step 1: 1-(Tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carbaldehyde (2-3)
[0275]To a stirred solution of pyrazole carboxaldehyde (2-1, 300 mg, 3.1 mmol) in tetrahydrofuran was sequentially added 3,4-dihydro-2H-pyran (2-2, 867 mg, 10.3 mmol) and catalytic amount of trifluoroacetic acid. The resulting solution was refluxed for 4 h and then cooled to rt. The reaction was quenched by addition of trace amount of sodium hydride. Solvent was removed under vacuum and the residue was purified by silica gel chromatography to give 2-3 (520 mg, 92%). MS (ESI+): m / z: 181.1 (M+H)+.
Step 2: (E)-5-Methoxy-2-(4-(2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)vinyl)-[2,4′-bipyrimidin]-2′-yl)isoindoline (2-4)
[0276]To a stirred solution of 1-7 (50 mg, 0.15 mmol) and tetrabutylammonium bromide (TBAB, 40 mg, 0.12 mmol) in 3 mL of dioxane was sequentially added 3 mL of 5 N NaOH(aq) and 2-3 (112 mg, 0.62 mmol). The reaction w...
example 3
(2′-(5-Methoxyisoindolin-2-yl)-[2,4′-bipyrimidin]-4-yl)vinyl)quinoline (Ex. 3)
[0278]
[0279]Prepared by following the same procedure described in Step 5 in Example 1. A yellow solid was obtained in 56% yield. 1H-NMR (300 MHz, CDCl3): δ (ppm): 9.03 (d, J=5.1 Hz, 1H), 8.99 (d, J=4.3 Hz, 1H), 8.84 (d, J=15.9 Hz, 1H), 8.67 (d, J=4.8 Hz, 1H), 8.32 (d, J=8.1 Hz, 1H), 8.22 (d, J=8.1 Hz, 1H), 7.75 (m, 4H), 7.48 (d, J=5.1 Hz, 1H), 7.41 (d, J=15.6 Hz, 1H), 7.26 (s, 1H), 6.90 (s, 1H), 6.87 (d, J=2.4 Hz, 1H), 5.06 (br, 4H), 3.85 (s, 3H). MS (ESI+): m / z: 459.3 (M+H)+.
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